Permeabilizing reagents to increase drug delivery and a method of local delivery

ABSTRACT

A composition and a method for increasing the permeability of membrane junctions or cell membranes for delivery of a drug to target tissues are disclosed. Also disclosed are methods and devices for local drug delivery.

CROSS REFERENCE

This is a divisional of U.S. patent application Ser. No. 09/997,706filed Nov. 30, 2001 now U.S. Pat. No. 6,663,880.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention involves compositions and methods for enhancingthe permeability of a vessel wall and/or cell membranes of individualcells to increase the uptake of a local drug delivery.

2. Description of the Background

Despite the general success of percutaneous transluminal interventionssuch as balloon angioplasty, high restenosis rates continue to be aproblem. Various techniques have been used to prevent restenosis,including the use of lasers, application of heat and the use ofintravascular stents. However, many of these techniques are still underinvestigation with mixed results, while others have generally not beensuccessful. Local drug delivery has the prospect of surpassing suchtechniques, provided sufficient drug uptake into the tissue can beobtained.

The treatment of cancerous tumors is another example of a treatment thatcould be improved by local drug delivery. In the treatment of tumors, anobjective is to administer the cancer drug so that it localizes as muchas possible in the tumor itself. Such drugs are commonly administeredsystemically through the blood stream. Various means are then utilizedfor causing the drug to bind to the cancerous tumor. Nevertheless,significant portions of the drug administered still circulate throughthe blood stream. As a result, noncancerous tissue may be affected bythe drug, causing undesirable side effects such a systemic toxicity.

A conventional way to deliver drugs locally has been to use a ballooncatheter. The balloon is made from a permeable or semipermeablematerial, which permits transport of the drug across the balloon surfaceas a result of an appropriate driving force. This driving force may beprovided by several different means. For example, an electricalpotential may be applied to the permeable or semipermeable membrane todrive ionic drugs or non-ionic drugs carried in an ionic solution acrossthe membrane in a process known as iontophoresis. Alternatively, highfrequency or ultra high frequency (ultrasonic) sound waves supplied by atransducer may be used to transport drugs across the semipermeablemembrane in a process known as phonophoresis or (synonymously)sonophoresis.

According to another concept, a modified catheter balloon designincludes a balloon having a pair of spaced inflatable lobes. After theballoon is properly positioned, the balloon lobes are inflated byintroducing an inflation medium (e.g., saline solution). Inflation ofthe balloon lobes causes the lobes to expand so that their outerperipheral portions engage the inner surfaces of the vessel walls. Thisengagement defines an open space, a drug treatment zone, between thelobes. A desired drug is then delivered to the open space, such that thedrug is in direct contact with the vessel wall.

According to yet another concept, a catheter is provided having a doublewalled balloon. An inner balloon is provided which is constructed froman impermeable material such as polyethylene. An outer balloon having apermeable or semipermeable membrane is generally concentric to the innerballoon and extends completely around the inner balloon. The outerballoon is first filled with drug. The inner balloon is then inflatedwith a standard inflation medium (e.g., saline solution). As a result ofinflation of the inner balloon, sufficient pressure is developed againstthe wall of the outer balloon (in contact with the vessel wall) to drivethe drug in the outer balloon through the wall of the outer balloon andtoward the vessel wall.

According to yet another concept, a stent can be used for the localdelivery of a drug. Implementation of local drug delivery via stents hasbeen achieved with the use of a polymeric matrix coated on the stent.The polymeric coating is impregnated with a drug for in vivo sustainedrelease of the drug.

These methods of local drug delivery are effective in placing a drug incontact with a vessel wall. However, the application of the drug appearsto be only superficial. In other words, the drug does not penetrate deepinto the tissues of the vessel wall, which is believed to be necessaryfor optimum results. To pose the problem more concretely, by way of oneexample, the etiology of restenosis is believed to be the excessivemigration and proliferation of vascular smooth muscle cells from thetunica media and adventatia layers of the vascular wall to the intimallayer. In order to efficaciously inhibit or treat restenosis, aneffective concentration of the drug must, accordingly, reach the vesselwall's outer layers. With the use of balloons and stents, the exposureof the drug is essentially limited to the intimal layer. Thepermeability of the vessel wall, therefore, needs to be increased forthe local delivery to the sub-layers.

SUMMARY OF THE INVENTION

In accordance with one aspect of the invention, a stent having aradially expandable tubular body and a coating, the coating including apermeabilizing reagent for increasing the permeability of membranejunctions or cell membranes, is disclosed. In one embodiment, thepermeabilizing reagent can be selected from the group consisting of acalcium ion chelator, a surfactant, and a receptor-mediatedpermeabilizing reagent. Furthermore, the permeabilizing reagent can beselected from the group consisting of iminodiacetic acid, nitriloaceticacid, ethylenediaminomonoacetic acid, ethylenediaminodiacetic acid,ethylenediaminotetraacetic acid, sodium taurodihydrofusidate, sodiumsalicylate, sodium caprate, sodium glycocholate, cholylsarcosine,isopropyl myristate, partially hydrolyzed triglycerides, fatty-acidsugar derivatives, oleic acid derivatives, histamine, bradykinin and itsconformational analogs, tumor necrosis factor alpha, nitroglycerine,sodium nitroprusside, diethylamine sodium, 3-morpholinosydnonimine,S-nitroso-N-acetyl-penicillamine, and vascular endothelial growth factorand combinations thereof.

In an embodiment, the coating can additionally include a P-glycoproteinsystem blocker. The P-glycoprotein system blocker can be selected fromthe group consisting of Pluronic P-85®, verapamil, disulfiram andantisense oligonucleotide complementary to a messenger RNA encodingP-glycoprotein and combinations thereof.

The coating, in addition, can include a drug. The drug can be selectedfrom the group consisting of antineoplastic, antimitotic,antiinflammatory, antiplatelet, antiallergic, anticoagulant, antifibrin,antithrombin, antiproliferative, antioxidant, antimigratory,antiextracellular matrix deposition, pro-apoptotic, nitric oxide donor,pro-angiogenic, and pro-arteriogenic substances and combinationsthereof. The coating may also include a polymer.

In accordance with an aspect of the invention, a method of forming acoating for a stent is disclosed, including applying a compositionincluding a permeabilizing reagent and a fluid, and essentially removingthe fluid from the composition on the stent to form the coating.

In accordance with another aspect, a method of delivering a drug througha membrane junction or a cell membrane is disclosed, includingdelivering a permeabilizing reagent to a membrane junction or a cellmembrane in a concentration sufficient to increase the permeability ofthe membrane junction or cell membrane, and delivering a drug to themembrane junction or cell membrane, whereby the drug travels through themembrane junction or cell membrane.

In one embodiment, the permeabilizing reagent is delivered by a stentand/or a catheter. Also, the drug can be delivered by a stent and/or acatheter.

The permeabilizing reagent, in addition, can be a solution including asolute selected from the group consisting of glucose, mannose, maltose,dextrose, fructose, sodium chloride, sodium citrate, sodium phosphate,polyethylene glycol, polyvinyl pyrrolidone and amino acids. Furthermore,the permeabilizing reagent can be selected from the group consisting ofiminodiacetic acid, nitriloacetic acid, ethylenediaminomonoacetic acid,ethylenediaminodiacetic acid, ethylenediaminotetraacetic acid, sodiumtaurodihydrofusidate, sodium salicylate, sodium caprate, sodiumglycocholate, cholylsarcosine, isopropyl myristate, partially hydrolyzedtriglycerides, fatty-acid sugar derivatives, oleic acid derivatives,histamine, bradykinin and its conformational analogs, tumor necrosisfactor alpha, nitroglycerine, sodium nitroprusside, diethylamine sodium,3-morpholinosydnonimine, S-nitroso-N-acetyl-penicillamine, and vascularendothelial growth factor and combinations thereof.

In accordance with an aspect, a composition for treating restenosis isdisclosed, including a permeabilizing reagent and a drug, wherein thepermeabilizing reagent increases the permeability of membrane junctionsor cell membranes of cells for the delivery of a drug to vasculartissues.

In accordance with another aspect, a method of inhibiting restenosis isdisclosed, including applying a permeabilizing reagent to endothelialcells and applying a drug to the area where the permeabilizing reagentis applied.

In accordance with yet another aspect of the present invention, a methodof local drug delivery is disclosed, including locally applying apermeabilizing reagent to a selected area of a body tissue, and locallyapplying a drug to the body tissue.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a partial cross-sectional view of an artery;

FIG. 2A is a schematic representation of a membrane of a cell lining avascular wall;

FIG. 2B is a schematic representation of the cell membrane of FIG. 2A,after having been exposed to a surfactant that has increased thepermeability of the cell membrane;

FIG. 3A is an enlarged view of the artery of FIG. 1, showing cellssurrounding a hyperosmotic solution present in the lumen of the arteryof FIG. 1;

FIG. 3B illustrates the cells of FIG. 3A, after they have reached anequilibrium with the hyperosmotic solution;

FIG. 4A illustrates cells having normal concentrations of intracellularcalcium ions (Ca⁺);

FIG. 4B illustrates the cells of FIG. 4A, wherein the concentration ofintracellular calcium ions (Ca⁺) has been significantly decreased;

FIG. 5 is a partial cross-sectional view of a balloon catheter fordelivering a permeabilizing reagent and/or a drug in accordance with oneembodiment of the invention;

FIG. 6 is a partial cross-sectional view of an alternative ballooncatheter for delivering a permeabilizing reagent and/or a drug inaccordance with a second embodiment of the invention;

FIG. 7 is a partial cross-sectional view of a drug infusion catheter fordelivering a permeabilizing reagent and/or a drug in accordance with athird embodiment of the invention;

FIG. 8 is a cross-sectional side view of a stent implanted in a vascularlumen;

FIG. 8A is a cross-sectional view of a strut of a stent having a polymercoating including two sublayers; and

FIG. 8B is a cross-sectional view of a strut of a stent, having apolymer coating, wherein a permeabilizing reagent and a drug areintermixed in the polymer coating.

DETAILED DESCRIPTION

1. Membrane Junctions

Although certain cell types—blood cells, sperm cells, and somephagocytic cells—are free within the body, may cells, particularly thoseof epithelial tissues, are knit into tight groups. FIG. 1 illustrates across section of an artery 2 showing some cell types that tend to formtight groups. The wall 4 of artery 2 is composed of three distinctlayers or tunics (as is the case with all blood vessels exceptcapillaries). These tunics surround a central blood-containing space ora lumen 6. The innermost tunic, which is in contact with blood flowingin lumen 6, is the tunica intima 8. Tunica intima 8 contains theendothelium 10, which lines the lumen of all vessels. Endothelium 10 iscomposed of endothelial cells, and is a continuation of the endocardiallining of the heart. The flat endothelial cells fit closely together,forming a slick surface that minimizes friction as blood moves throughlumen 6. In vessels larger than about 1 mm in diameter, a subendotheliallayer 12 of loose connective tissue lies beneath endothelium 10. Amiddle layer is the tunica media 14, which is composed of smooth musclecells. The outermost layer is tunica adventitia 16, which is composedlargely of loosely woven collagen fibers. Surrounding tunica adventitia16 is smooth muscle cell tissue 18.

Adjacent endothelial cells in tunic intima 8 are joined laterally inpart by membrane junctions including tight junctions, desmosomes and gapjunctions. Although the membrane junctions bind cells close together,the fit is not absolute and therefore there is some extracellular spacebetween the cells known as intercellular clefts.

The membrane junctions not only provide a mechanical bond between cells,but they may provide selective transport mechanisms to allow theendothelial cells to take up nutrients, natural hormones, and othercompounds. The membrane junctions, however, can prevent some moleculesfrom passing through the extracellular space between adjacent cells ofan epithelial membrane. While the barrier function of tight junctions isdesirable, for example, in the case where the blood has becomecontaminated by bacterial infection, it is undesirable when attemptinglocal intravascular drug delivery. It therefore would be advantageous inmany clinical situations to increase the permeability of the membranejunctions.

2. Cell Membranes

In addition to the membrane junctions, another barrier to drug deliverycould be the cell membranes of individual cells. FIG. 2A illustrates atypical cell membrane 40, as would be found, for example, in the cellsforming the endothelial cell lining a vascular lumen 6. Cell membrane 40can act as a barrier to cytoplasm 38. Cell membrane 40 is composedmainly of a lipid bilayer 42, but also has a large number of proteinmolecules 44 protruding through lipid bilayer 42. Lipid bilayer 42 is afilm of lipids only two molecules thick that is continuous over theentire cell surface.

Lipid bilayer 42 is composed almost entirely of phospholipids 41 andcholesterol 43. One portion of the phospholipid 41 and cholesterol 43molecules is soluble in water (hydrophilic) and another portion of eachof these molecules is soluble only in fats (hydrophobic). Because thehydrophobic portions of phospholipid 41 and cholesterol 43 molecules arerepelled by water but mutually attracted to each other, they have atendency to line up as illustrated in FIG. 2A, with the fatty portions46 in the center of lipid bilayer 42 and the hydrophilic portions 48projecting away from the center of lipid bilayer 42.

Lipid bilayer 42 is almost entirely impermeable to water andwater-soluble substances such as ions, glucose, urea, and others.However, fat-soluble substances, such as oxygen, carbon dioxide andalcohol, can penetrate this portion of membrane 40.

An important feature of this lipid bilayer is that it is a lipid fluidand not a solid. Therefore, portions of the membrane can flow from onepoint to another in the membrane. For example, proteins floating in thelipid bilayer 42 tend to diffuse to all areas of the cell membrane 40.

As FIG. 2A illustrates, there are globular masses floating in lipidbilayer 42. These are membrane proteins. The membrane proteins includeintegral proteins 44. Like the lipids, the integral proteins 44 have afat-soluble portion and a water-soluble portion. However, integralproteins 44 usually have a water-soluble portion on both ends and afat-soluble portion in the middle. Integral proteins 44 providestructural pathways through which water and water-soluble substances,especially ions, can diffuse between the extracellular fluid andintracellular fluid. Peripheral proteins 45 are normally attached to oneof the integral proteins 44. Peripheral proteins 45 function primarilyas enzymes.

Membrane carbohydrates 50 may be attached to proteins or lipids of cellmembrane 40, and enter into immune system reactions. Membranecarbohydrates 50 often act as receptor substances for binding hormones,such as insulin, that stimulate specific types of activity in the cells.

The rate of membrane penetration by a solute (e.g., drug molecules) isdependent on a variety of factors. These include molecular size of thesolute (permeability generally decreases with increasing size), lipidsolubility (permeability usually increases with increasing fat or oilstability), and degree of ionization (permeability generally decreaseswith increased ionization). The diffusion gradient for the solute acrossthe cell membrane also is of great importance. Other factors that caninfluence transport of a solute include temperature and pH of theextracellular fluid. If these factors and others associated with aparticular drug delivery scheme are unfavorable, the rate of membranepenetration by the drug molecules could be very low. It therefore wouldbe advantageous in many clinical situations to increase the permeabilityof the cell membranes of target cells.

3. Increased Permeability

The term “increased permeability,” as used herein, is defined as havinga property of allowing an increased mass of a drug to travel through acellular barrier relative to a cellular barrier that has not beenexposed to a permeabilizing reagent. “Cellular barrier” refers to acellular structure such as a membrane junction and/or a cell membranethat acts to inhibit drug movement into or between cells that wouldotherwise occur through, for example, active or passive diffusion.“Membrane junction” refers to a-junction between cell membranes ofadjacent cells such as tight junctions, desmosomes and gap junctions.“Cell membrane” refers to the plasma membrane that encloses a cell'scontents such as the cytoplasm and nucleus. For example, the mass ofdrug taken up by the permeabilized vascular endothelium could be two toten times greater than a vascular endothelium not contacted by apermeabilizing reagent. For brevity, the embodiments of this inventionare explained with reference to the vascular endothelium, although thepermeabilizing reagents may increase the permeability of other layers ofcells or cell types. Also, the practice of the invention should not belimited to vascular use and the application of the present invention isequally applicable to other tissues or cell linings, such as for thedelivery of the drug to the esophagus, urethra, or other biologicaltissues.

A permeabilizing reagent can be applied to the luminal wall in aconcentration sufficient to increase the permeability of the endotheliumand/or cell membranes. The application of the reagent is concomitantlyor subsequently followed by the administration of a drug to allow thedrug to penetrate into the cytoplasm or pass the endothelium lining orother cell build-up, such as cell build-up caused by restenosis. Manydifferent types of compounds may be used as permeabilizing reagents, andvarious devices may be used to deliver the permeabilizing reagent and/orthe drug. Moreover, the invention has many different clinicalapplications.

An effective amount of the permeabilizing reagent will increase thepermeability of the vessel wall and/or cell membranes of individualcells such that sufficient quantities of a drug may pass from within thevasculature into the cytoplasm of individual cells, or through theendothelium and into the adjacent target tissue, where it can exert atherapeutic effect. It is anticipated that a relatively small volume(e.g., 5 mL or less) of permeabilizing reagent is required to achievethis increased permeability.

The amount of drug administered in conjunction with, or afteradministration of, the permeabilizing reagent is determined on anindividual basis and is based, at least in part, on consideration of theindividual's size, the specific disease, the severity of the symptoms tobe treated, the result sought, and other factors. Standardpharmacokinetic test procedures employing laboratory animals todetermine dosages are understood by one of ordinary skill in the art.

4. Classes of Permeabilizing Reagents and Their Effects on the Cell

4A. Hyperosmotic Solutions

Hyperosmotic solutions may be used to temporarily alter the size andshape of the endothelial cells of the vascular wall. Referring now toFIG. 3A, following administration of a solution containing an osmoticagent (in a concentration high enough to provide sufficient osmolality),lumen 6 of artery 2 has a solute concentration higher than the soluteconcentration inside individual endothelial cells 20 (three of which arelabelled as 20A, 20B, and 20C). Due to osmosis, water from within allindividual endothelial cells will pass inward toward lumen 6, therebydiluting the fluid in lumen 6. As a result, the endothelial cellssurrounding lumen 6 shrink in size, as illustrated in FIG. 3B,increasing the size of the intercellular clefts. Due to the shrinking ofthe endothelial cells, tissues underlying the endothelial cells areexposed, providing an avenue between endothelial cells for the exposureof a locally provided drug to the media, adventitia and preiadventitialayers.

Since the osmotic agent administered may be excreted by the kidneys ormetabolized by other cells in the body, the shrinkage of the endothelialcells by hyperosmotic shock is only a temporary phenomenon (e.g., lessthan an hour in duration). Therefore, for short duration infusions, asingle bolus of a hyperosmotic solution should be sufficient. For longerduration treatment, the osmotic agent may be mixed into the formulationof the drug.

A wide range of compounds are capable of acting as osmotic agents whichwill shrink the endothelial cells. Of course, the osmolality of a givenosmotic agent must be considered. For example, a sodium chlorideconcentration of 0.9% is approximately iso-osmotic with body fluids.Thus, sodium salts having a concentration greater than 0.9% would behyperosmotic relative to the interior of an endothelial cell, and wouldbe expected to cause the endothelial cells lining the vascular wall totemporarily shrink. Similarly, a 5% glucose solution is approximatelyiso-osmotic with body fluids. Thus, sugar solutions greater than 5% inconcentration are likewise hyperosmotic relative to the interior of suchan endothelial cell, and likewise would be expected to cause theendothelial cell to temporarily shrink.

In principle, any hyperosmotic solution of a biocompatible substance issuitable for use as a permeabilizing reagent. Examples of usefulhyperosmotic solutions include solutions of glucose, mannose, maltose,dextrose, fructose and other sugars. Also useful are salt solutions,such as sodium chloride, sodium citrate, and sodium phosphate. Solutionsof biocompatible polymers, such as polyethylene glycol (PEG) andpolyvinyl pyrrolidone (PVP) and solutions of amino acids are alsouseful.

4B. Calcium Ion Chelators

Referring to FIGS. 4A and 4B, tight junctions between endothelial cells20 lining the vascular wall are controlled by chemical signals that aremediated by calcium ion concentration. When calcium ion concentrationsdecrease, the tight junctions between endothelial cells are opened.Providing a substance that captures calcium ions in the vascular lumencan cause the tight junctions between the endothelial cells to open.Substances that capture calcium ions are known as “calcium ionchelators.”

Examples of calcium ion chelators useful for this purpose includeiminodiacetic acid (IDA), nitriloacetic acid (NTA),ethylenediaminomonoacetic acid (EDMA), ethylenediaminodiacetic acid(EDDA), and ethylenediaminotetraacetic acid (EDTA). Extensive literatureis available concerning the use of EDTA, because it is used as anexcipient in many drug compositions. In one embodiment, theconcentration of calcium ion chelator in the blood required to decreaseintracellular calcium ion concentrations can be from about 0.01 mM to 1M, for example about 1 mM.

4C. Surfactants

In accordance with one embodiment of the invention, a surfactant is usedas the permeabilizing reagent. Referring to FIG. 2A, when a surfactantis delivered to a target tissue adjacent to a vascular lumen, by, forexample, a stent or catheter, surfactant molecules insert themselvesthrough the outer surface of cell membrane 40, effectively disruptingthe dense structure of cell membrane 40 and fluidizing it. The nowfluidized cell membrane 40 becomes more permeable (illustratively shownby openings 52 of FIG. 2B). Molecules of a locally delivered drug (e.g.,paclitaxel or heparin) can permeate through cell membrane 40.Application of the drug simultaneously with the reagent may be moreeffective as the duration of permeability is short in time.

Both ionic and non-ionic surfactants may be used in accordance with theinvention. Examples of useful ionic surfactants include sodiumtaurodihydrofusidate, sodium salicylate, sodium caprate, and sodiumglycocholate. Examples of useful non-ionic surfactants includecholylsarcosine, isopropyl myristate, partially hydrolyzedtriglycerides, fatty-acid sugar derivatives, and oleic acid derivatives.These surfactants may be administered in concentrations ranging from0.0001% to 10%, more narrowly about 0.001 to 1%, by example about 0.1%.Although ionic surfactants tend to be slightly more effective influidizing the membrane, they also tend to be slightly more irritating.

4D. Receptor-Mediated Permeabilizing Reagents

Receptor-mediated permeabilizing reagents also increase the permeabilityof the membrane of endothelial cells to a drug through their interactionwith receptors located on the surface of the endothelial cells of thevascular wall. The interaction between these receptors and thereceptor-mediated permeabilizing reagents is presently believed to alterjunctional or transport properties between the cells, thereby increasingthe permeability of the cell membrane to drug molecules such asantineoplastic, antiinflammatory, and antiplatelet drug molecules.Examples of such receptor-mediated permeabilizing reagents includehistamine, bradykinin and its conformational analogs, and tumor necrosisfactor alpha (TNF-alpha). TNF-alpha appears to work through a nitricoxide (NO) mediated mechanism, and any compound that increases the localpresence of NO, such as nitroglycerine, sodium nitroprusside (SNP),diethylamine sodium (DEA), 3-morpholinosydnonimine (SIN-1), andS-nitroso-N-acetyl-penicillamine (SNAP), is expected to have an effectsimilar to that of the effect of TNF-alpha. Vascular endothelial growthfactor (VEGF) likewise increases the local presence of nitric oxide andnitroprusside, and thus is another such receptor-mediated permeabilizer.

In one exemplary embodiment, histamine and bradykinin can be used atconcentrations between 0.01 mM and 0.1M, for example about 100 mM.TNF-alpha should be used at very low concentrations, for example between0.00001% and 1%, or alternatively between 0.01% and 0.1%. NO donors canbe used at higher concentrations, ranging from 0.01 mM to 1 M,or between1 mM and 0.1 M.

4E. P-glycoprotein System Blockers Alone or in Conjunction with OtherPermeabilizing Reagents

One known mechanism by which certain drugs function is by theirinteraction with a protein that is variously called Multidrug-Resistance1 protein (MDR 1), Pleiotropic-glycoprotein (P-glycoprotein), P-gp, orP170. Herein, it is referred to as “P-glycoprotein.” P-glycoprotein isendogenous in cell membranes, including certain drug resistant cells,multidrug resistant tumor cells, gastrointestinal tract cells, and theendothelial cells that form the blood-brain barrier. P-glycoproteininteracts with certain machinery of the cell in a “P-glycoproteinsystem.” The P-glycoprotein system acts as an efflux pump for the cell.By providing P-glycoprotein system “blockers,” which interfere with theefflux pump action of the P-glycoprotein system, a drug is permitted toenter and remain in the cell and exert its desired effect.

Such P-glycoprotein system blockers include, but are not limited to, thesurfactant Pluronic P-85® (commercially available from BASF Corporation,Mount Olive, N.J.), the blood pressure medication verapamil, or theanti-alcohol drug disulfiram. In addition, an antisense oligonucleotidecomplementary to a messenger RNA encoding P-glycoprotein may also be useused to block the P-glycoprotein system. To achieve the desired effect,the P-glycoprotein system blocker can be co-administered with a drug,such that the P-glycoprotein system blocker is present at concentrationsranging from 0.001% solution to 10% (w/v), and more typically atconcentrations ranging from 0.1% to 3%.

In accordance with another embodiment of the invention, a permeabilizingreagent other than a P-glycoprotein system blocker is administered first(e.g., an osmotic agent, a calcium ion chelator, a surfactant, and/or areceptor-mediated permeabilizing reagent), followed by administration ofthe antisense oligonucleotide complementary to the messenger RNAencoding P-glycoprotein at a few selected cells. The firstpermeabilizing reagent may provide an avenue by which the antisenseoligonucleotide may enter the target cell. Once the antisenseoligonucleotidc is in place in the cell, it prevents the synthesis ofP-glycoprotein. Because the cells produce significantly lessP-glycoprotein than normal, the P-glycoprotein system for given cellscan be disabled for long periods of time. As a result, drugs may beadministered to these cells without being exposed to the efflux pumpingaction of the P-glycoprotein system, and thus will reside in those cellsfor a longer period of time, increasing the likelihood that the drugwill exert its therapeutic effect.

5. Drugs that may be used in Coniunction with Permeabilizing Reagents

Depending on the type of permeabilizing reagent selected, the drug to betaken up into the target tissue surrounding the vascular endothelium maybe administered before, or more usefully, simultaneously with or afteradministration of the permeabilizing reagent. For example, since thepermeabilizing effect of a hyperosmotic solution on the vascularendothelium may last a few hours, the drug may be administered afteradministration of the hyperosmotic solution. In contrast, if asurfactant is used as the permeabilizing reagent, the drug may beco-administered, since the permeabilizing effect of a surfactant is moretransient.

The drug can be for inhibiting the activity of vascular smooth musclecells. More specifically, the drug can be aimed at inhibiting abnormalor inappropriate migration and/or proliferation of smooth muscle cellsfor the inhibition of restenosis. The drug can also include anysubstance capable of exerting a therapeutic or prophylactic effect inthe practice of the present invention. For example, the drug can be forenhancing wound healing in a vascular site or improving the structuraland elastic properties of the vascular site. Examples of drugs includeantiproliferative substances such as actinomycin D, or derivatives andanalogs thereof (manufactured by Sigma-Aldrich 1001 West Saint PaulAvenue, Milwaukee, Wis. 53233; or COSMEGEN available from Merck).Synonyms of actinomycin D include dactinomycin, actinomycin IV,actinomycin I₁, actinomycin X₁, and actinomycin C₁. The drug can alsofall under the genus of antineoplastic, anti-inflammatory, antiplatelet,anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic,antiallergic, antioxidant and antimigratory substances. Examples of suchantineoplastics and/or antimitotics include paclitaxel (e.g. TAXOL® byBristol-Myers Squibb Co., Stamford, Conn.), docetaxel (e.g. Taxotere®,from Aventis S.A., Frankfurt, Germany) methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g.Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples ofsuch antiplatelets, anticoagulants, antifibrin, and antithrombinsinclude sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, and thrombininhibitors such as Angiomax ä (Biogen, Inc., Cambridge, Mass.). Examplesof such cytostatic or antiproliferative agents include angiopeptin,angiotensin converting enzyme inhibitors such as captopril (e.g.Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.),cilazApril or lisinopril (e.g. Prinivil® and Prinzide® from Merck & Co.,Inc., Whitehouse Station, N.J.); calcium channel blockers (such asnifedipine), colchicine, fibroblast growth factor (FGF) antagonists,fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (aninhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand nameMevacor® from Merck & Co., Inc., Whitehouse Station, N.J.), monoclonalantibodies (such as those specific for Platelet-Derived Growth Factor(PDGF) receptors), nitroprusside, phosphodiesterase inhibitors,prostaglandin inhibitors, suramin, serotonin blockers, steroids,thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), andnitric oxide. An example of an antiallergic agent is permirolastpotassium. The drug can also fall under the genus of antiextracellularmatrix deposition, pro-apoptotic, nitric oxide donor, pro-angiogenic,and pro-arteriogenic substances. Other drugs which may be appropriateinclude alpha-interferon, genetically engineered epithelial cells,rapamycin and dexamethasone.

6. Devices Providing Local Delivery of Permeabilizing Reagent and/orDrug to a Target Tissue

In accordance with the invention, the permeabilizing reagent may bedelivered to the target tissue by a variety of devices, including, butnot limited to, balloon catheters, drug infusion catheters, and stents.

6A. Balloon Catheters

FIG. 5 shows local delivery of a permeabilizing reagent to a targettissue 60 adjacent to a vascular wall 62 (e.g., the wall of an artery)through a balloon 74 of an intravascular balloon catheter assembly.Balloon 74 is mounted on a catheter body 71 that may be advanced over aguidewire 67 to a position adjacent to the desired treatment site, whichis denoted as target tissue 60. Balloon 74 includes an inner dilatationballoon 66 and an outer balloon 68. Inner dilatation balloon 66 isconstructed from a material that is substantially impermeable. Innerdilatation balloon 66 includes an inner chamber 70 which is connectedthrough an inner balloon lumen 72 to the proximal end of the catheter.Outer balloon 68 is generally concentric to inner dilatation balloon 66and extends completely around inner dilation balloon 66. Outer balloon68 is constructed from a permeable or semipermeable material andincludes a balloon chamber 76 formed between the outer surface ofdilatation balloon 66 and the inner surface of balloon 68. Balloonchamber 76 is connected through an outer balloon lumen 78 to a proximalend of the catheter.

To locally deliver a permeabilizing reagent and/or drug, catheter body71 is advanced through the vascular system until balloon 74 is adjacentto target tissue 60. In one embodiment of the method, chamber 76 ofouter balloon 68 is first filled with a permeabilizing reagent. This maybe achieved, for example, using an Indeflator® syringe containing avolume of permeabilizing reagent in fluid communication with lumen 78 ofouter balloon 68. Chamber 70 of inner balloon 66 is then inflated with astandard inflation medium (e.g., saline solution) provided through lumen72. In this manner, permeabilizing reagent contained in outer balloon 68passes through outer balloon 68 and travels radially into contact withvascular wall 62 adjacent to target tissue 60. A sufficient amount ofpermeabilizing reagent is delivered to increase the permeability of theendothelial cells that form vascular wall 62. After a sufficient amountof permeabilizing reagent is delivered to achieve increased permeabilityof the endothelial cells lining vascular wall 62, a drug is locallyprovided to vascular wall 62 adjacent target tissue 60.

According to another embodiment of the method, the permeabilizingreagent and drug are delivered simultaneously through outer balloon 68.

In another embodiment of the invention, illustrated in FIG. 6, adouble-lobed balloon 80 is used that has a pair of spaced inflatableballoon lobes 82 and 84. These lobes 80 and 84 are connected by a commoninterior chamber 86, which is in turn connected to a balloon lumen 88extending to the proximal end of the catheter. A supply lumen 90 extendsto the proximal end of the catheter and is in fluid communication withan area 92 formed between inflated balloon lobes 82 and 84.

After balloon 80 is properly positioned adjacent to target tissue 60,balloon lobes 82 and 84 are inflated by introducing an inflation medium(e.g., saline) through lumen 88 and into interior chamber 86. Thisinflation causes lobes 82 and 84 to expand so that their outerperipheral portions engage vascular wall 62 adjacent to target tissue60. This engagement defines a treatment zone 92 between lobes 82 and 84.A permeabilizing reagent is then introduced through lumen 90 and intotreatment zone 92 so that the permeabilizing reagent is in directcontact with the endothelial cells of vascular wall 62. Followingadministration of a sufficient concentration of the permeabilizingreagent to achieve the increased permeability of vascular wall 62, adrug is administered through lumen 90 and into treatment zone 92. Thedrug can come into contact with the target tissue through the increasedpermeability of vascular wall 62.

6B. Drug Infusion Catheters

In yet another embodiment of the invention, a drug infusion catheter,rather than a balloon catheter, is used to deliver the permeabilizingreagent and/or the drug. An example of such a drug infusion catheter isshown in FIG. 7. In general, a catheter assembly 100 includes anelongated tubular body 102 having an outer tubular member 104 and aninner tubular member 106 concentrically disposed within outer tubularmember 104 and defining an annular lumen 108 therebetween. Inner tubularmember 106 is adapted to receive a guidewire 110 which facilitates theadvancement of catheter assembly 100 to place an operative distalportion 112 thereof at a desired site in the patient's vascular system.Outer tubular member 104 is provided with a plurality of flowpassageways 114 in operative distal portion 112, which are spaced alongthe length thereof. The transverse cross-sectional area, i.e., thedischarge area, of passageways 114 increases with each successivepassageway in the distal direction. Uniform spacing between thecenterline of individual passageways 114 is provided. Advantageously,this design provides a uniform flow of permeabilizing reagent and/ordrug to the exterior of outer tubular member 104. This feature may beparticularly desirable, for example, in local delivery of a small volumeof a drug at low flow rates (e.g., 0.1–1.5 mL/hr).

The proximal end of catheter assembly 100 is provided with a two-armadapter 116, having one arm 118 for introducing permeabilizing reagentand/or drug into annular lumen 108 and another arm 120 for directingguidewire 110 into a lumen 122 within inner tubular member 106.

A flexible tip 124 is provided on the distal end of tubular body 102 tolessen the trauma caused by the introduction of the catheter into thepatient's blood vessel. The tip is formed of a softer, more resilientplastic material than either inner tubular member 106 or outer member104. Flexible tip 124 closes off and seals the distal end of annularlumen 108. Further details regarding this drug delivery catheter may befound in commonly assigned U.S. Pat. No. 5,021,044.

Of course, the balloon catheter design and drug infusion catheterdesigns discussed above are merely exemplary; other catheter designs,and indeed other local delivery devices, may be used in accordance withthe invention.

6C. Drug Delivery Stents

According to another embodiment of the present invention, both thepermeabilizing reagent and/or the drug of interest are locally deliveredby a drug delivery stent. It should be understood by one of ordinaryskill in the art that a variety of application routes are possible. Forexample, both the drug and reagent can be applied via a stent.Alternatively, the reagent can be applied by the catheter or balloon andthe drug applied via the stent. Yet in another embodiment, the reagentcan be administered systemically and the drug applied via the stent.

FIG. 8 illustrates an exemplary drug delivery stent implanted in avascular lumen 130 defined by vascular wall 131. A stent 132 includes aplurality of struts 134. Struts 134 define a generally cylindrical stentbody having an outer surface in contact with the vascular wall 131 andan inner surface in contact with a fluid stream 140 flowing throughlumen 130.

FIG. 8A illustrates a cross-sectional view of strut 134 of stent 132. Apolymer layer 142 can be deposited on the outer surface of strut 134.Polymer layer 142 includes a first sublayer 144 (e.g.,polycaprolactone), which contains a permeabilizing reagent 146, and isdisposed above a second sublayer 148 (e.g., polysiloxane), whichcontains a drug 150. Two distinct layers are useful, since thecomposition of the polymer layer may be selected to influence the rateof release of the permeabilizing reagent or drug. With such a layeringof permeabilizing reagent 146 and drug 150 in sublayers 144 and 148,essentially all of the permeabilizing reagent 146 is released from stent132 before drug 150 is released from stent 132. Accordingly, theendothelial cells of the vascular wall will have increased permeabilityso that drug 150 may be delivered in increased concentration to targettissue 133.

In yet another embodiment, illustrated in FIG. 8B, permeabilizingreagent 146 and drug 150 are intermixed in a single polymer layer 142 soas to effect a simultaneous local delivery of permeabilizing reagent 146and drug 150 to the endothelial cells of vascular wall 131.

Of course, in embodiments where a stent is used to locally deliver boththe permeabilizing reagent and the drug, certain compatibility factorsmust be considered. It is essential that the polymer, the permeabilizingreagent, and the drug be mutually compatible. Moreover, the polymer andthe permeabilizing reagent should not chemically alter the therapeuticnature of the drug.

Representative examples of polymers that can be used to coat a stent inaccordance with the present invention include ethylene vinyl alcoholcopolymer (commonly known by the generic name EVOH or by the trade nameEVAL), poly(hydroxyvalerate); poly(L-lactic acid); polycaprolactone;poly(lactide-co-glycolide); poly(hydroxybutyrate);poly(hydroxybutyrate-co-valerate); polydioxanone; polyorthoester;polyanhydride; poly(glycolic acid); poly(D,L-lactic acid); poly(glycolicacid-co-trimethylene carbonate); polyphosphoester; polyphosphoesterurethane; poly(amino acids); cyanoacrylates; poly(trimethylenecarbonate); poly(iminocarbonate); copoly(ether-esters) (e.g. PEO/PLA);polyalkylene oxalates; polyphosphazenes; biomolecules, such as fibrin,fibrinogen, cellulose, starch, collagen and hyaluronic acid;polyurethanes; silicones; polyesters; polyolefins; polyisobutylene andethylene-alphaolefin copolymers; acrylic polymers and copolymers; vinylhalide polymers and copolymers, such as polyvinyl chloride; polyvinylethers, such as polyvinyl methyl ether; polyvinylidene halides, such aspolyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile;polyvinyl ketones; polyvinyl aromatics, such as polystyrene; polyvinylesters, such as polyvinyl acetate; copolymers of vinyl monomers witheach other and olefins, such as ethylene-methyl methacrylate copolymers,acrylonitrilestyrene copolymers, ABS resins, and ethylene-vinyl acetatecopolymers; polyamides, such as Nylon 66 and polycaprolactam; alkydresins; polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxyresins; polyurethanes; rayon; rayon-triacetate; cellulose; celluloseacetate; cellulose butyrate; cellulose acetate butyrate; cellophane;cellulose nitrate; cellulose propionate; cellulose ethers; andcarboxymethyl cellulose.

Examples of stents include self-expandable stents, balloon-expandablestents, and stent-grafts. The underlying structure of the stent can beof virtually any design. The stent can be made of a metallic material oran alloy such as, but not limited to, cobalt chromium alloy (ELGILOY),stainless steel (316L), “MP35N,” “MP20N,” ELASTINITE (Nitinol),tantalum, nickel-titanium alloy, platinum-iridium alloy, gold,magnesium, or combinations thereof. “MP35N” and “MP20N” are trade namesfor alloys of cobalt, nickel, chromium and molybdenum available fromstandard Press Steel Co., Jenkintown, Pa. “MP35N” consists of 35%cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consistsof 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum. Stents madefrom bioabsorbable or biostable polymers could also be used with theembodiments of the present invention

7. Treatment of Disease

The methods and structures shown herein may be used for the treatment ofvarious diseases. “Treatment of disease” includes: (i) preventing thedisease, that is, causing the clinical symptoms of the disease not todevelop; (ii) inhibiting the disease, that is, arresting the developmentof clinical symptoms; and/or (iii) relieving the disease, that is,causing the regression of clinical symptoms. For example, the presentinvention may be used to treat ischemia. Such a treatment may includeselecting an (ischemic) target tissue, and contacting an arterial walladjacent the target tissue with a balloon catheter containing EDTA. Aproangiogenic or pro-arteriogenic drug, such as VEGF, is then introducedto the arterial wall through the balloon catheter.

In accordance with another aspect of the invention, the presentinvention may be used for the treatment of restenosis. For example, forthe purpose of preventing restenosis, an anti-proliferative drug (e.g.,rapamycin or decetaxel) can be administered. In conjunction or prior tothe administration of the drug, the surfactant sodiumtaurodihydrofusidate is administered as a permeabilizing reagent.

While particular embodiments of the present invention have been shownand described, those skilled in the art will appreciate that changes andmodifications can be made without departing from the invention in itsbroader aspect. For example, many balloon catheters, drug infusioncatheters and stents are useful in practicing the invention. Manydifferent combinations of permeabilizing agents and drugs are possible.Therefore, the appended claims are to encompass within their scope allsuch changes and modifications as fall within the scope of thisinvention.

1. A method of delivering a drug through a membrane junction or a cellmembrane comprising: delivering a permeabilizing reagent to a membranejunction or a cell membrane in a concentration sufficient to increasethe permeability of the membrane junction or cell membrane; anddelivering a drug to the membrane junction or cell membrane, wherein thedrug travels through the membrane junction or cell membrane.
 2. Themethod of claim 1, wherein the permeabilizing reagent is delivered by astent and/or a catheter.
 3. The method of claim 1, wherein the drug isdelivered by a stent and/or a catheter.
 4. The method of claim 1,wherein the permeabilizing reagent is a solution including a soluteselected from the group consisting of glucose, mannose, maltose,dextrose, fructose, sodium chloride, sodium citrate, sodium phosphate,polyethylene glycol, polyvinyl pyrrolidone and amino acids.
 5. Themethod of claim 1, wherein the permeabilizing reagent is selected fromthe group consisting of iminodiacetic acid, nitriloacetic acid,ethylenediaminomonoacetic acid, ethylenediaminodiacetic acid,ethylenediaminotetraacetic acid, sodium taurodihydrofusidate, sodiumsalicylate, sodium caprate, sodium glycocholate, cholylsarcosine,isopropyl myristate, partially hydrolyzed triglycerides, fatty-acidsugar derivatives, oleic acid derivatives, histamine, bradykinin and itsconformational analogs, tumor necrosis factor alpha, nitroglycerine,sodium nitroprusside, diethylamine sodium, 3-morpholinosydnonimine,S-nitroso-N-acetyl-penicillamine, and vascular endothelial growth factorand combinations thereof.
 6. A method of local drug delivery,comprising: locally applying a permeabilizing reagent to a selected areaof a body tissueto increase the permeability of a cellular barrier; andlocally applying a drug to the body tissue.
 7. The method of claim 6,wherein the permeabilizing reagent is applied before or concomitantlywith the drug.
 8. The method of claim 6, wherein the local applicationof the permeabilizing reagent and the drug are via a stent.
 9. Themethod of claim 6, wherein the permeabilizing reagent is selected fromthe group consisting of a hyperosmotic solution, a calcium ion chelator,a surfactant, and a receptor-mediated permeabilizing reagent.
 10. Themethod of claim 6, additionally including applying a P-glycoproteinsystem blocker.
 11. The method of claim 10, wherein the application ofThe P-glycoprotein system blocker follows application of thepermeabilizing reagent.
 12. The method of claim 10, wherein theP-glycoprotein system blocker is selected from the group consisting ofPluronic P-85®, verapamil, disulfiram and antisense oligonucleotidecomplementary to a messenger RNA encoding P-glycoprotein andcombinations thereof.
 13. The method of claim 6, wherein the drug isselected from the group consisting of antineoplastic, antimitotic,antiflammatory, antiplatelet, antiallergic, anticoagulant, antifibrin,antithrombin, antiproliferative, antioxidant, antimigratory,antiextracellular matrix deposition, pro-apoptotic, nitric oxide donor,pro-angiogenic, and pro-arteriogenic substances and combinationsthereof.
 14. A method of delivering a drug through a membrane junctionor a cell membrane comprising: delivering a hyperosmotic solution, acalcium ion chelator, a surfactant, and/or a receptor-mediatedpermeabilizing reagent to a membrane junction or a cell membrane in aconcentration sufficient to increase the permeability of the membranejunction or cell membrane; and delivering a drug to the membranejunction or cell membrane, wherein the drug travels through the membranejunction or cell membrane.
 15. A method of local drug delivery,comprising: (a) locally applying a hyperosmotic solution, a calcium ionchelator, a surfactant, and/or a receptor-mediated permeabilizingreagent to a selected area of a body tissue to increase the permeabilityof a cellular barrier; and (b) locally applying a drug to the bodytissue.
 16. A method of local drug delivery, comprising: locallyapplying a P-glycoprotein system blocker to a selected area of a bodytissue; and locally applying a drug to the body tissue.
 17. The methodof claim 16, further comprising locally applying a permeabilizingreagent to the body tissue.
 18. The method of claim 17, wherein thepermeabilizing reagent is applied before the P-glycoprotein systemblocker.
 19. The method of claim 17, wherein the permeabilizing reagentis selected from the group consisting of a hyperosmotic solution, acalcium ion chelator, a surfactant, and a receptor-mediatedpermeabilizing reagent.
 20. The method of claim 16, wherein theP-glycoprotein system blocker is selected from the group consisting ofPluronic P-85®, verapamil, disulfiram and antisense oligonucleotidecomplementary to a messenger RNA encoding P-glycoprotein andcombinations thereof.
 21. The method of claim 16, wherein theP-glycoprotein system blocker or the drug is carried by a stent.
 22. Amethod of delivering a drug through a membrane junction or a cellmembrane comprising: delivering a hyperosmotic solution to a membranejunction or a cell membrane in a concentration sufficient to increasethe permeability of the membrane junction or cell membrane; anddelivering a drug to the membrane junction or cell membrane, wherein thedrug travels through the membrane junction or cell membrane.
 23. Themethod of claim 22, wherein the hyperosmotic solution is delivered by acatheter.
 24. The method of claim 22, wherein the drug is delivered by astent and/or a catheter.
 25. The method of claim 22, wherein thehyperosmotic solution includes a solute selected from the groupconsisting of glucose, mannose, maltose, dextrose, fructose, sodiumchloride, sodium citrate, sodium phosphate, polyethylene glycol,polyvinyl pyrrolidone and amino acids.
 26. A method of local drugdelivery, comprising: positioning a stent at a selected area of a bodytissue, the stent carrying a permeabilizing reagent to increase thepermeability of a cellular barrier; and locally applying a drug to thebody tissue.
 27. The method of claim 26, wherein the permeabilizingreagent is selected from the group consisting of iminodiacetic acid,nitriloacetic acid, ethylenediaminomonoacetic acid,ethylenediaminodiacetic acid, ethylenediaminotetraacetic acid, sodiumtaurodihydrofusidate, sodium salicylate, sodium caprate, sodiumglycocholate, cholylsarcosine, isopropyl myristate, partially hydrolyzedtriglycerides, fatty-acid sugar derivatives, oleic acid derivatives,histamine, bradykinin and its conformational analogs, tumor necrosis,factor alpha, nitroglycerine, sodium nitroprusside, diethylamine sodium,3-morpholinosydnonimine, S-nitroso-N-acetyl-penicillamine, and vascularendothelial growth factor and combinations thereof.
 28. The method ofclaim 26, wherein the stent is positioned before or during theapplication of the drug.
 29. The method of claim 26, wherein the localapplication of the drug is via a stent.
 30. The method of claim 26,wherein the permeabilizing reagent is selected from the group consistingof a calcium ion chelator, a surfactant, and a receptor-mediatedpermeabilizing reagent.
 31. The method of claim 26, wherein the stentadditionally carries a P-glycoprotein system blocker.
 32. The method ofclaim 31, wherein the P-glycoprotein system blocker is selected from thegroup consisting of Pluronic P-85®, verapamil, disulfiram and antisenseoligonucleotide complementary to a messenger RNA encoding P-glycoproteinand combinations thereof.
 33. The method of claim 26, wherein the drugis selected from the group consisting of antineoplastic, antimitotic,antiinflammatory, antiplatelet, antiallergic, anticoagulant, antifibrin,antithrombin, antiproliferative, antioxidant, antimigratory,antiextracellular matrix deposition, pro-apoptotic, nitric oxide donor,pro-angiogenic, and pro-arteriogenic substances and combinationsthereof.
 34. The method of claim 26, wherein the permeabilizing reagentis carried by a polymeric coating on the stent.
 35. The method of claim26, wherein the stent additionally carries the drug.
 36. The method ofclaim 35, wherein the stent carries the permeabilizing reagent and thedrug in a coating, wherein the coating includes the permeabilizingreagent in a first layer and the drug in a second layer.
 37. A method oflocal drug delivery, comprising: positioning a stent at a selected areaof a body tissue, the stent carrying a drug; and locally applying apermeabilizing reagent to the body tissue to increase the permeabilityof a cellular barrier.
 38. The method of claim 37, wherein thepermeabilizing reagent is selected from the group consisting ofiminodiacetic acid, nitriloacetic acid, ethylenediaminomonoacetic acid,ethylenediaminodiacetic acid, ethylenediaminotetraacetic acid, sodiumtaurodihydrofusidate, sodium salicylate, sodium caprate, sodiumglycocholate, cholylsarcosine, isopropyl myristate, partially hydrolyzedtriglycerides, fatty-acid sugar derivatives, oleic acid derivatives,histamine, bradykinin and its conformational analogs, tumor necrosis,factor alpha, nitroglycerine, sodium nitroprusside, diethylamine sodium,3-morpholinosydnonimine, S-nitroso-N-acetyl-penicillamine, and vascularendothelial growth factor and combinations thereof.
 39. The method ofclaim 37, wherein the permeabilizing reagent is applied before or duringpositioning of the stent.
 40. The method of claim 37, wherein the localapplication of the permeabilizing reagent is via a stent.
 41. The methodof claim 37, wherein the permeabilizing reagent is selected from thegroup consisting of a hyperosmotic solution, a calcium ion chelator, asurfactant, and a receptor-mediated permeabilizing reagent.
 42. Themethod of claim 37, wherein the stent additionally carries aP-glycoprotein system blocker.
 43. The method of claim 42, wherein theP-glycoprotein system blocker is selected from the group consisting ofPluronic P-85®, verapamil, disulfiram and antisense oligonucleotidecomplementary to a messenger RNA encoding P-glycoprotein andcombinations thereof.
 44. The method of claim 37, wherein the drug isselected from the group consisting of antineoplastic, antimitotic,antiinflammatory, antiplatelet, antiallergic, anticoagulant, antifibrin,antithrombin, antiproliferative, antioxidant, antimigratory,antiextracellular matrix deposition, pro-apoptotic, nitric oxide donor,pro-angiogenic, and pro-arteriogenic substances and combinationsthereof.
 45. The method of claim 37, wherein the drug is carried by apolymeric coating on the stent.
 46. The method of claim 37, wherein thestent additionally carries the permeabilizing reagent.
 47. The method ofclaim 46, wherein the stent carries the permeabilizing reagent and thedrug in a coating, wherein the coating includes the permeabilizingreagent in a first layer and the drug in a second layer.
 48. The methodof claim 1, wherein the permeabilizing reagent is selected from thegroup consisting of a hyperosmotic solution, a calcium ion chelator, asurfactant, and a receptor-mediated permeabilizing reagent.
 49. Themethod of claim 6, wherein the local application of the permeabilizingreagent is via a catheter and the local application of the drug is via astent.
 50. The method of claim 15, wherein steps (a) and (b) areperformed via a stent.
 51. The method of claim 15, wherein step (a) isperformed via a catheter and step (b) is performed via a stent.
 52. Themethod of claim 16, wherein the local application of the P-glycoproteinsystem blocker and the local application of the drug are via a stent.53. The method of claim 16, wherein the local application of theP-glycoprotein system blocker is via a catheter and the localapplication of the drug is via a stent.
 54. The method of claim 37,wherein the permeabilizing reagent is a solution including a soluteselected from the group consisting of glucose, mannose, maltose,dextrose, fructose, sodium chloride, sodium citrate, sodium phosphate,polyethylene glycol, polyvinyl pyrrolidone and amino acids.